As discussed in U.S. Pat. No. 6,846,481, malaria is caused by parasitic protozoa of the genus Plasmodium, and is responsible for approximately two-million deaths each year worldwide. Current control efforts are focused on the mosquito vector, and treatment of the disease with anti-malarial drugs. No vaccine is yet available. Over the past four decades, the parasite has become increasingly resistant to many anti-malarial drugs and an effective vaccine is seen as a promising means for controlling morbidity and mortality caused by this pathogen. Most of the candidate molecules from Plasmodium suggested for inclusion in a vaccine are proteins that bind to receptors of host target cells. Necessary for vaccine development is the identification and characterization of the role played by these proteins. Unfortunately, this effort has been hampered by difficulties in procuring enough parasite protein to allow thorough study. Several heterologous expression systems have been utilized but none has proven to be ideal, especially for the production of functional protein.
A variety of agents have been proposed for the treatment of malaria. Many of these agents have distinct disadvantages, including the ability of the malarial parasite to develop drug resistance to the agents.
Since the discovery of quinine, a variety of agents utilizing various biochemical mechanisms have been used to treat malaria. For example, dihydrofolate reductase inhibitors (e.g., diaminopyrimidines), oxygen-reduction mediators (e.g., primaquine), and antibacterial agents (e.g., sulphonamides) have been administered to treat the disease.
Existing agents have or have had their place in the therapeutic armamentarium with varying degrees of success, however, several types of deficiencies can be identified in the available drugs currently available for the treatment of malaria. In particular, since 1960 the transmission of malaria has risen in most regions where the infection is endemic, and chloroquine-resistant and multi-drug resistant strains of, e.g., P. falciparum, have spread. In addition, current anti-malarial drugs are typically accompanied by side effects, including rash, vomiting, diarrhea, fever and headache (atovaquone and mefloquine); cardiovascular and CNS effects (chloroquine); and blood dyscrasias (pyrimethamine and primaquine). Pharmacokinetics are typically sub-optimal with long half life values (e.g., atovaquone, 1.5-3 days; chloroquine, days to weeks; pyrimethamine, 80-95 hours; mefloquine, 20 days), excessive protein binding (e.g., 99% with atovaquone; ˜98% with mefloquine), double peaking (e.g., atovaquone), massive volumes of distribution (chloroquine over 100 l/kg; mefloquine, several times the volume of body water), and erratic and incomplete absorption of oral doses.
Provided is a novel mechanistic approach to antimalarial drugs by inactivation of the microtubules of P. falciparum and P. vivax, as a component of the search for treatments with, for example, lesser risk of resistance, better safety profiles, and optimized pharmacokinetic properties.
Of the current drugs on the market used to treat malaria, none specifically target the plasmodial microtubules involved in mitosis. Microtubules are cylindrical organelles that play critical roles in mitosis, transport and cell mobility. They contain the protein tubulin. Tubulin molecules line up into protofilaments, thirteen (13) of which are arranged side to side to form the microtubule. In mitosis, the chromosomes are attached to microtubules, which constitute the mitotic spindle. In cell transport, organelles being moved are carried along the microtubule by motor proteins such as dynein or kinesin. A key aspect of microtubule function is the fact that microtubules exhibit dynamic behavior, in other words, they constantly grow and shrink. Targeting tubulin has been a successful strategy in the search for drugs for cancer, e.g. paclitexel (taxol) and the Vinca alkaloids. They work by inhibiting dynamic behavior, causing cells to undergo apoptosis. Only 2-5 drug molecules per microtubule are typically needed.